Iridium-Catalyzed Borylation of Primary Benzylic C-H Bonds without a Directing Group: Scope, Mechanism, and Origins of Selectivity

Article abstract of DOI:10.1021/jacs.5b04899

Primary benzylic boronate esters are useful intermediates in organic synthesis, but these reagents cannot be prepared by hydroboration. The benzylic C-H borylation of methylarenes would be a method to form these products, but such reactions without neat methylarene or a directing group are unknown. We report an approach to divert the borylation of methylarenes from aromatic positions to benzylic positions with a silylborane as reagent and a new iridium catalyst containing an electron-deficient phenanthroline as ligand. This system forms benzylic boronate esters selectively over the corresponding aryl boronate esters. An Ir diboryl monosilyl complex ligated by the phenanthroline was isolated and determined to be the resting state of the catalyst. Mechanistic studies show that this complex is kinetically competent to be an intermediate in the catalytic process. Kinetic studies of benzylic and aryl C-H borylation catalyzed by various Ir complexes show that the rate of aryl C-H borylation decreases with decreasing electron density at the metal center of the Ir catalyst, but that the rate of benzylic C-H borylation is less sensitive to the degree of electron density at the metal center of the Ir catalyst. Kinetic and computational studies suggest that the two borylation reactions respond differently to the degree of electron density at the metal center because they occur with different turnover-limiting steps. The turnover-limiting step in the borylation of aryl C-H bonds is known to be C-H oxidative addition, but the turnover-limiting step of the borylation of benzylic C-H bonds appears to be an isomerization prior to C-B reductive elimination.

Full text of DOI:10.1021/jacs.5b04899

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Article
Iridium-Catalyzed Borylation of Primary Benzylic C-H Bonds Without
a Directing Group: Scope, Mechanism, and Origins of Selectivity
Matthew A Larsen, Conner V. Wilson, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b04899 • Publication Date (Web): 15 Jun 2015
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Journal of the American Chemical Society
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Iridium-Catalyzed Borylation of Primary Benzylic C-H Bonds With-
out a Directing Group: Scope, Mechanism, and Origins of Selectivity
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Matthew A. Larsen, Conner V. Wilson, and John F. Hartwig
Department of Chemistry, University of California, Berkeley, California, 94720.
ABSTRACT: Primary benzylic boronate esters are useful intermediates in organic synthesis, but these reagents cannot be prepared
by hydroboration. The benzylic C-H borylation of methylarenes would be a method to form these products, but such reactions
without neat methylarene or a directing group are unknown. We report an approach to divert the borylation of methylarenes from
the aromatic position to the benzylic position with a silylborane as reagent and a new iridium catalyst containing an electron-
deficient phenanthroline as ligand. This system forms benzylic boronate esters selectively over the corresponding aryl boronate
esters. An Ir diboryl monosilyl complex ligated by the phenanthroline was isolated and determined to be the resting state of the
catalyst. Mechanistic studies show that this complex is kinetically competent to be an intermediate in the catalytic process. Kinetic
studies of benzylic and aryl C-H borylation catalyzed by various Ir complexes show that the rate of aryl C-H borylation decreases
with decreasing electron-density at the metal center of the Ir catalyst, but that the rate of benzylic C-H borylation is less sensitive to
the degree of electron-density at the metal center of the Ir catalyst. Kinetic and computational studies suggest that the two boryla-
tion reactions respond differently to the degree of electron-density at the metal center because they occur with different turnover-
limiting steps. The turnover-limiting step in the borylation of aryl C-H bonds is known to be C-H oxidative addition, but the turno-
ver-limiting step of the borylation of benzylic C-H bonds appears to be an isomerization prior to C-B reductive elimination.
boronate esters requires the intermediacy of a benzylic halide
or pseudohalide, which are formed by the radical halogenation
of a methylarene.
INTRODUCTION
Organoboron compounds are versatile intermediates in or-
ganic synthesis for the formation of carbon-carbon and car-
bon-heteroatom bonds. Such reagents have become essential
building blocks for the synthesis of materials, pharmaceuti-
cals, and agrochemicals.1-4 Arylboronic acids and the analo-
gous esters and trifluoroborate salts are the most commonly
used organoboron compounds. Commercial sources for these
compounds are abundant, and methods for the synthesis of
compounds containing the arylboron unit are well developed.
However, the commercial availability of alkylboron com-
pounds is more limited.
Scheme 1. Methods for the synthesis of primary benzylic
boronate esters
Metalation/Quech:
a)
B(OR)3, then pinacol
M
Bpin
R
R
M = Li, MgBr
Cross-Coupling:
B2pin2
Pd, Ni, Cu, Fe
b)
X
Bpin
Like arylboronate esters, alkylboronate esters are often syn-
thesized by quenching an organolithium or organomagnesium
compound with a trialkylborate, followed by transesterifica-
tion with a chelating diol (Scheme 1a).5 Although this method
often forms boronate esters in high yield, it has limited func-
tional group compatibility, due to the high reactivity of organ-
olithium and organomagnesium species. The borylation of
organic halides first developed by Ishiyama and Miyaura,6,7
and elaborated by others,8-13 is a milder method to convert aryl
and alkyl halides directly to the desired organoboronate ester
(Scheme 1b); however, the scope and yield of these reactions
are often lower for the synthesis of alkyl boronate esters than
for the synthesis of aryl boronate esters, and the halide must be
present in the organic reactant of this process.
R
R
M = Br, Cl, OTs
C-H Functionalization:
B2pin2 or HBpin
c)
Pd, Rh
CH3
Bpin
R
R
neat
Limited Scope
Iridium-catalyzed borylation of C-H bonds has created a
route to arylboronate esters without the intermediacy of aryl
electrophiles.3,16,17 We envisioned a direct synthesis of primary
benzylic boronate esters from methylarenes, but this approach
faces the challenge of directing the borylation to a benzylic C-
H bond over typically more reactive aryl C-H bonds. Although
the selective borylation of benzylic C-H bonds has been
achieved with Pd,18 or Rh catalysts,19,20 these methods have
poor functional group tolerance and require a large excess of
methylarene (Scheme 1c). Ir-catalyzed borylation of primary
and secondary benzylic C-H bonds has been reported with a
Although alkyl boronate esters are often prepared by hy-
droboration of an alkene,14,15 this method cannot be used to
form primary benzylic boronate esters. Such benzylic boronate
esters are synthetically valuable because they can be converted
to biologically relevant diarylmethanes, benzylic amines, and
benzyl alcohols. Typically, the synthesis of primary benzylic
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Page 2 of 12
hydrosilyl directing group,21,22 but the undirected, iridium-
tion with L6 containing electron-deficient aryl rings at the 3
1
2
catalyzed borylation of benzylic C-H bonds with high ben-
zylic:aryl (Bn:Ar) selectivity is unknown.
and 8 positions on the phen core led to the highest ratio of
2a:2b (4:1, Entry 6) in favor of the benzylboronate ester.
3
4
5
6
7
8
9
In 2008, our group reported that the borylation of toluene
solvent with Et3SiBpin catalyzed by iridium and di-tert-
butylbipyridine as ligand gives a 1:1 mixture of benzyl-
boronate esters to arylboronate esters.23 Although this selectiv-
ity was poor, it did suggest that the selective borylation of a
benzylic C-H bond could be achieved.
Table 1. Effect of Ligand and Solvent on the Borylation of
benzylic and aryl C-H bondsa
Et3SiBpin 1 equiv
[Ir(COD)OMe]2 1 mol%
Ligand 2 mol%
Cl Me
+
Cl
Me
Cl
Bpin
Solvent, 100 ºC
16 h
We report the selective borylation of benzylic C-H bonds in
methylarenes with Et3SiBpin, catalyzed by an Ir complex con-
taining an electron-poor phenanthroline. These reactions occur
with good functional group tolerance, require only a small
excess of methylarene, and do not require a directing group.
The benzylic boronate esters formed from this reaction can be
converted to benzylic alcohols, benzylic amines, dia-
rylmethanes, and benzylic iodides. Mechanistic studies reveal
the resting state of the catalyst and show that the borylation of
aryl C-H bonds is much more sensitive to the electronic prop-
erties of the catalyst than is the borylation of benzylic C-H
bonds, most likely because of a difference in rate-determining
step. This difference in electronic effects on the two processes
created an opportunity to distinguish between the two sites for
C-H borylation by the basicity of the dative ligand.
1.5 equiv
2a
2b
Bpin
10
11
12
13
14
15
16
17
18
19
20
21
22
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1
Entry
Ligand
Solvent
Yield 2ab
Yield 2bb
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L6
L6
L6
THF
THF
29%
24%
34%
5%
31%
49%
40%
34%
26%
13%
13%
6%
THF
THF
THF
44%
52%
42%
60%
60%
THF
Dioxane
Cyclohexane
Methylcyclohexane
6%
O
O
N
tBu
tBu
Me
Me
RESULTS AND DISCUSSIONS
Me
Me
N
N
N
N
N
N
Development of Conditions for Benzylic Borylation. To
create a catalyst and reagent for the borylation of benzylic C-H
bonds, we built upon our preliminary observations of benzyl-
boronate esters forming as one product from the reaction of
toluene with Et3SiBpin catalyzed by iridium ligated by di-tert-
butylbipyridine. We investigated reactions of m-chlorotoluene
(1) with Et3SiBpin catalyzed by a series of phenanthrolines
possessing different steric and electronic properties. We used
m-chlorotoluene 1 as a model substrate because the reaction of
this neat arene with Et3SiBpin catalyzed by iridium ligated by
di-tert-butylbipyridine (dtbpy) gave a roughly 1:1 ratio of
products from borylation at the benzylic position and 5-
position of the arene, allowing the effect of the ligand on the
selectivity for reaction at benzyl and aryl C-H bonds to be
determined readily.
N
L1
L4
L2
L3
R
R
R
N
N
Me
Me
R
L5 R = Me; L6 R = CF3
b
aReactions were conducted on a 0.125 mmol scale. Deter-
mined by GC analysis.
The selectivity was improved further by changing the sol-
vent. Reactions in alkane solvents (Entries 8-9), rather than
ethereal solvents, such as THF and dioxane (Entries 6-7), oc-
curred with a selectivity that more strongly favored the ben-
zylboronate ester (2a:2b = 10:1). The reactions in cyclohexane
and methylcyclohexane (MeCy) occurred with the same selec-
tivity. Thus, we conducted our further studies with MeCy as
solvent because its boiling point is higher than that of cyclo-
hexane and matches the reaction temperature.
The results of reactions conducted with a series of ligands
are shown in Table 1. These reactions were conducted with 1.5
equivalents of arene, instead of the neat arene.23 With THF as
solvent and dtbpy (L1) as ligand, benzylic boronate 2a and
aryl boronate 2b were formed in equal quantities (Table 1,
Entry 1). The reaction of 3-chlorotoluene catalyzed by the
complex containing tmphen (L2) as ligand (recently shown to
create a more reactive catalyst for the borylation of arenes,24,25
heteroarenes,26 and alkanes27-30 than those containing dtbpy)
led to a significantly smaller amount of product 2a from ben-
zylic borylation (Table 1, Entry 2). Thus, we tested catalysts
containing less electron-donating nitrogen ligands. The reac-
tion with phendione (L3) as ligand (Table 1, Entry 3) occurred
with selectivity similar to that with L1 as ligand. The lowest
selectivity for product 2a was observed for the reaction with
neocuprine (L4) as ligand (Table 1, Entry 4), suggesting that a
sterically congested environment around the metal center fa-
vors the formation of arylboronate 2b over the benzylboronate
2a. However, the reactions conducted with 3,8-
diarylphenanthrolines L5 and L6 as ligand (Table 1 Entries 5-
6) formed the benzylboronate 2a as the major product. Reac-
With the conditions in entry 9 of Table 1, we began to in-
vestigate the scope of the borylation of methylarenes. Howev-
er, the reactions of methylarenes containing substituents other
than alkyl groups or halogens formed benzylic boronate esters
in low yield. These low yields appeared to result from a long
induction period (observed to be >10 h in most cases), rather
than an incompatibility of the substrate with the catalyst. Thus,
further changes to the catalyst were necessary to create a pro-
cess that occurred with broad scope.
To decrease the induction period, we developed a new
precatalyst that could more readily enter the catalytic cycle
than the combination of [Ir(COD)OMe]2, L6, and silylborane.
Because the active catalyst likely contains at least one silyl
ligand, a precatalyst that contains a silyl ligand might generate
the active catalyst more rapidly than does [Ir(COD)OMe]2.
Also, a precatalyst that contains the dative ligand L6 could
form the active species more readily than would a combination
of L6 and an Ir precursor.
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Journal of the American Chemical Society
F3C
CF3
1
2
3
4
5
Et3SiBpin 1 equiv
Conditions A or B
L6 1 equiv.
then Et3SiH 10 equiv
SiEt3
Me
Cl
Cl
N
N
H
Bpin
[Ir(COE)2Cl]2
0.5 equiv.
Ir
(1)
Cl
MeCy, 100 ºC
THF
2
3
1.5 equiv
79% isolated
yield
CF3
1
2a
F3C
6
Conditions A: [Ir(COD)OMe]2 1 mol%, L6 2 mol%; Conditions B: 3, 2 mol%
7
8
9
0.25!
0.2!
10
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0.15!
Conditions A!
Conditions B!
0.1!
0.05!
0!
0!
20000!
40000!
Time sec.!
60000!
80000!
Figure 2. Reaction profiles for the borylation of 1 with Et3SiBpin
catalyzed by conditions A or conditions B. Reactions were con-
ducted on a 0.25 mmol scale. The concentration of 2a was deter-
mined by GC analysis.
Figure 1. Structure of complex 3 determined by X-ray diffraction.
Hydrogen atoms have been omitted, except for the hydrides
bound to iridium.
Cl
Me
Cl
Bpin
To generate such a precatalyst, we combined a 1:1 mixture
of ½[Ir(COE)2Cl]2 and L6 in THF with 10 equivalents of tri-
ethylsilane (Eq. 1). A brown/purple solid was isolated from
this solution and was characterized by NMR spectroscopy, IR
+
Et3SiBpin
complex 3 1 mol%
2a
2b
Bpin
Bpin
Me
Cl
Cl
(2)
Cl
Bpin
+
1
Methylcyclohexane
100 ºC
spectroscopy, and combustion analysis. The H NMR spec-
1
Bpin
trum contained one set of signals that is consistent with chlo-
ro-hydrido-silyl complex 3. However, X-ray crystallographic
analysis showed that, in the solid-state, the product adopted
the structure of the unsymmetrical dimer shown in Figure 1. In
this structure, each metal center is bound to a terminal chloride
or a terminal hydride, and the two metal centers are bridged by
a chloride ligand and a hydride ligand. Consistent with this
assertion, the infrared spectra of 3 (nujol mull) contains a
sharp absorption at 2121 cm-1 (due to the terminal hydride)
and a very broad absorption at 1841 cm-1 (due to the bridging
hydride).31 In the IR spectrum of the Ir-D analogue of 3, these
peaks shifted, confirming that they originated from Ir-H
stretching modes (see SI, pp. S7-S8). The IR spectrum of 3 in
THF contained both Ir-H peaks, suggesting that 3 exists as the
dimer in solution and that the bridging and terminal hydride
and chloride ligands rapidly exchange with each other.
4a
Cl
Bpin
+
Bpin
+
4b
4c
Bpin
Bpin
The graph in Figure 3 summarizes the effect of the ratio of
arene to Et3SiBpin on the distribution of products 2a-b and 4a-
c. For reactions conducted with limiting arene, less than 60%
yield of benzylic boronate 2a formed; instead, they formed
significant quantities of polyborylated compounds 4a-c. For
reactions conducted with limiting silylborane, the yield of the
desired product 2a increased with increasing ratio of
arene:Et3SiBpin. However, no increase in the yield of 2a was
observed when the reaction was conducted with a ratio of
arene to Et3SiBpin higher than 1.5:1. Thus, we conducted the
remainder of the study with a ratio of arene to Et3SiBpin of
1.5:1.
We compared the profile of the borylation of 1 catalyzed by
the combination of [Ir(COD)OMe]2 and L6 (Figure 2, Condi-
tions A) to that of the borylation of 1 catalyzed by complex 3
(Figure 2, Conditions B). Under conditions A, we observed a
long induction period. However, under conditions B, the reac-
tion was complete after 1 hour with no observable induction
period.
With this new precatalyst in hand, we investigated the mass
balance of the reaction and the effect of the ratio of arene to
Et3SiBpin on the distribution of products. GC/MS analysis of
the reaction mixture from the borylation of 1 with Et3SiBpin,
catalyzed by 3 showed that two products from diborylation of
the arene and one product of triborylation were present, in
addition to the products of monoborylation 2a and 2b. One
diborylated compound was shown to be 4a (Eq. 2) after its
isolation from the reaction mixture. The other diborylated
product was shown to be 4b, and the triborylation product was
determined to be 4c, by independent synthesis.
3
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curred in lower yield and selectivity than the borylation of
1
2
3
4
5
6
7
8
meta or para-substituted methylarenes. For example, o-
chlorotoluene formed benzylic boronate 5p in 35% isolated
yield with only 3:1 (Bn:Ar) selectivity. However, a similar
methylarene containing one additional chloro group at the
para-position reacted to form benzylic boronate 5q in 68%
yield with complete selectivity for the benzylic boronate. This
result shows that high yields and selectivity are attained if the
aryl ring is sufficiently substituted to inhibit competing aryl C-
H borylation, even when the steric properties of a substituent
ortho to the methyl group undergoing borylation may hinder
benzylic borylation.
2a
2b
Limiting
Arene
Limiting
Silylborane
9
4a + 4b
4c
Total Yielda
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chart 1. Scope of the Benzylic Borylation of Methylarenesa
Et3SiBpin 1 equiv
complex 3 1 mol%
(Het)Ar-CH3
1.5 equiv
(Het)Ar
Bpin
MeCy, 100 ºC
Arene:Et3SiBpin Ratio
R
Bpin
Bpin
Figure 3. Effect of arene:Et3SiBpin ratio on product distribution
for the benzylic borylation of 1. Reactions conducted on a 0.125
mmol scale. aTotal yield based on moles of boron incorporated for
the limiting silylborane regime and on the moles of arene for the
limiting arene regime. Yields determined by GC analysis.
R
Product
R
H
Bn:Ar
9:1
Yield
51%
Product
R
Bn:Ar Yield
>99:1 67%
5a
2a
5b
5c
5d
5i
5j
iPr
Cl
82:1
63%
Cl
Br
I
11:1
9.1:1
6.3:1
45:1
53%
50%
35%
57%
38%b
41%b
50%
49%b
Scope of the Borylation of Primary Benyzlic C-H Bonds.
The scope of the benzylic borylation was assessed under the
reaction conditions shown in Chart 1. Methylarenes containing
a variety of functional groups reacted with Et3SiBpin catalyzed
by 1-2 mol% of 3 at 100 °C in methylcyclohexane to form the
corresponding benzylic boronate esters in moderate to excel-
lent yields. (The reactions were conducted for 16 h, but many
of the reactions were complete in less than an hour.) The reac-
tions of toluene and meta-substituted methylarenes formed
moderate yields of benzylic boronates 5a-5h with good to
excellent selectivity for the benzylic boronate over the aryl
boronate. Halogens, methoxy, carboalkoxy, carbamoyl, and
dialkylamino groups were all tolerated.
5k C(O)OMe 23:1 61%b
5l
OMe
SiMe3
OCF3
CF3
1.7:1
>99:1 73%
31:1 57%
35%b
5m
5n
5o
Me
5e C(O)OMe 2.7:1
>99:1 62%
5f
C(O)NEt2 10:1
Bpin
Bpin
5g
5h
OMe
5.6:1
41:1
5oa, 73%c
NMe2
F3C
Cl
Me
Bpin
Bpin
Bpin
The yield and selectivity of the benzylic boronate ester from
the reactions of para-substituted methylarenes were higher
than those observed from the reactions of meta-substituted
methylarenes. With the exception of boronate 5l, benzylic
boronate esters 5i-5o were formed in ≥23:1 (Bn:Ar) selectivity
and were isolated in yields ranging from 57-73%. This higher
selectivity results from the greater steric hindrance at each aryl
C-H bond of a 1,4-substituted arene than at the 5-position of a
1,3- or 1,2,3-substituted arene.
Cl
Cl
Me
5p, 35%
3:1 (Bn:Ar)
5q, 68 %
>99:1 (Bn:Ar)
5r, 54%
>99:1 (Bn:Ar)
α
Cl
Bpin
Br
Bpin
Me
MeO
Bpin
Br
β
Me
O
5u, 52%d
>99:1 (Bn:Ar)
6.3:1 (α:β)
5s, 61%
14:1 (Bn:Ar)
5t, 69%
40:1 (Bn:Ar)
In general, the substituent para to the methyl undergoing
borylation had a strong effect on the rate and selectivity of the
reaction. For example, the borylation of p-methylanisole
formed product 5l slowly, and the selectivity for the benzylic
product was only 1.7:1 (Bn:Ar). The reaction of p-
(dimethylamino)toluene with Et3SiBpin in the presence of 10
mol% of complex 3 did not even form observable products
from borylation. However, the reaction of p-methyl benzotri-
fluoride formed benzylic boronate 5o in 62% yield, and even
generated significant quantities of bisboryl product in less than
one hour. Bisboryl product 5oa formed in 73% yield by con-
ducting the reaction of 1 equivalent of p-methyl benzotrifluo-
ride with 3 equivalents of silylborane, catalyzed by 4 mol% of
complex 3.
Bpin
F
Bpin
Bpin
Br
F
5v, 80%
19:1 (Bn:Ar)
5w, 56%
4.3:1 (Bn:Ar)
5x, 87%
>99:1 (Bn:Ar)
5y, R = Bpin; 60%b,e; isolated mixture 4:1 (Bn:Ar)
5z, R = OH; 40%f
R
Cl
N
Cl
aReactions were conducted on a 0.500 mmol scale. Yields are for
isolated benzylic boronate ester. Selectivity determined by GC
b
c
analysis. Reaction conducted with 2 mol% of complex 3. Reac-
tion conducted with 1 eq of arene, 3 eq of Et3SiBpin, and 4 mol%
of complex 3. dIsolated as a 6.3:1 (α:β) mixture of products.
eFormed inseparable mixture of aryl and benzylic boronate esters.
Ortho-substituted methylarenes also formed the correspond-
ing benzylic boronate esters. However, these reactions oc-
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Journal of the American Chemical Society
fMixture of products 5y was treated with aqueous NaOH and H2O2
in THF, and pyridyl methanol 5z was isolated.
chlorotoluene, methyl p-toluate, and p-methylanisole with
1
2
3
4
5
6
7
8
B2pin2 catalyzed by the combination of [Ir(COD)OMe]2 and
dtbpy (IMH catalyst, Conditions A, Chart 2). In contrast to the
borylation of p-substituted methylarenes under our current
conditions (Chart 2, Conditions B), the borylation of p-
substituted methylarenes under Conditions A formed benzylic
boronate esters in low yield and selectivity. For example, the
borylation of methyl p-toluate under Conditions A formed the
benzylic boronate 5k in only 35% yield with selectivity less
than 2:1 (Bn:Ar), whereas the same reaction under Conditions
B formed 5k in 63% yield with only trace amounts of compet-
ing arene borylation. Likewise, the borylation of p-
chlorotoluene and p-methylanisole under Conditions A formed
products 5j and 5l in 9% yield and <1% yield, respectively,
but the borylation of the same substrates formed benzyl-
boronates 5j and 5l in 63% yield and 35% yield, respectively,
under conditions B.
The borylation of substrates containing two different methyl
substituents occurred at the less hindered of the methyl groups.
For example, the borylation of 2-bromo-1,4-dimethylbenzene
occurred at the methyl group meta to the bromo substituent (α
product) in preference to the methyl group ortho to the bromo
substituent (β product). The ratio of these two products 5u was
6.3:1 (α:β).
9
The borylation of methylnaphthalenes formed naphthylme-
thyl boronate esters 5v and 5w in good to excellent yields.
Even though 2-methylnaphthalene possesses two sterically
accessible aryl C-H bonds, naphthylmethyl boronate 5v was
formed in 80% yield with 19:1 (Bn:Ar) selectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The borylation of methylarenes containing fluoride substit-
uents formed benzylic boronates, albeit with lower selectivity
(Bn:Ar) than did the borylation of methylarenes containing
other electron-withdrawing groups. For example, the boryla-
tion of p-fluorotoluene formed the product of aryl C-H boryla-
tion at the site adjacent to fluorine as the major product. How-
ever the borylation of fluorinated methylarenes in which all
aryl C-H bonds are adjacent to at least one substituent larger
than fluorine occurred in excellent yield and with high selec-
tivity. For example, the borylation of 4-bromo-2,6-difluoro-
toluene formed benzylic boronate 5x in 87% yield. No aryl C-
H borylation or bisborylation was observed in this reaction.
Chart 2. Comparison of Catalysts for Borylation of p-
Substituted Methylarenesa
Conditions A
or Conditions B
Me
Bpin
R
R
Conditions A: [Ir(COD)OMe]2 1 mol%, dtbpy 2 mol%,
B2pin2 1 equiv, arene 1 equiv, THF, 80 ºC
Conditions B: Complex 3 1 mol%, Et3SiBpin 1 equiv,
arene 1.5 equiv, methylcyclohexane, 100 ºC
Bpin
Bpin
The reaction of picolines with Et3SiBpin catalyzed by 3 did
not form the corresponding heteroaryl or pyridylmethyl boro-
nate ester except when the substrate contained substituents
adjacent to nitrogen. We hypothesized that steric bulk adjacent
to nitrogen in picolines might discourage coordination of the
pyridine to the catalyst. Indeed, the borylation of 2,6-dichloro-
3-picoline formed the pyridylmethyl boronate as the major
product. We were unable to separate the heteroaryl and pyri-
dylmethyl boronate products; therefore, 5y was isolated as a
4:1 (Bn:Ar) mixture of isomers. However, pyridyl methanol 5z
was isolated in pure form in 40% yield after treatment of the
initial mixture 5y with H2O2 and NaOH.
Bpin
MeO
Cl
MeO
5j
5k
5l
O
A: 9% (38%)
B: 63% (<5%)
A: 37% (25%)
B: 63% (<5%)
A: 0% (57%)
B: 35% (20%)
aReactions were conducted on a 0.250 mmol scale. Yields were
determined by GC analysis. Yields in parentheses are for the
combined yield of all aryl boronate ester products.
Functionalization of Primary Benzylic Boronate Esters.
To illustrate the synthetic utility of primary benzylic boronate
esters formed by the borylation of methylarenes, we conducted
several reactions (Scheme 2) of naphthylmethyl boronate 5v.
Amination of 5v under reaction conditions developed by
Morken et al33 formed N-Boc-2-(aminomethyl)-naphthalene
6a in 49% yield. Oxidation of 5v with hydrogen peroxide
formed 2-(hydroxymethyl)naphthalene 6b in quantitative
yield. Inspired by recent work from Morken showing that bis-
boryl alkanes can be activated with t-butoxide to form reactive
nucleophiles for alkylation,34 monobenzylboronate 5v was
treated with KOtBu and quenched with iodine to give 2-
(iodomethyl)-naphthalene 6c in 86% yield. So far, reactions of
the monobenzylboronate with alkyl halides under these condi-
tions did not occur.
In general, electron-deficient methylarenes reacted faster
than electron-rich methylarenes. However, the selectivity for
the benzylic boronate ester over the arylboronate ester was
often lower for reactions of electron-deficient methylarenes
than for reactions of electron-rich methylarenes. For example,
the lowest selectivity for the borylation of m-substituted
methylarenes was observed for the borylation of methyl m-
toluate. This reaction formed 5e with only 2.7:1 (Bn:Ar) selec-
tivity, whereas the borylation of 3-dimethylaminotoluene
formed benzylic boronate 5h over the aryl boronate in a 41:1
(Bn:Ar) ratio. These results suggest that the rate of aryl C-H
borylation is more sensitive to the electronic properties of the
methylarene than is the rate of benzylic C-H borylation. A
more detailed investigation of this phenomenon will be pre-
sented later in this paper.
The most conventional application of an organoboronate es-
ter is Suzuki coupling to form diarylmethanes, but few exam-
ples of the coupling of primary benzylic boronate esters with
aryl bromides have been reported.35 Thus, we surveyed a series
of bases and catalysts to identify a suitable protocol for cou-
pling of the products of the benzylic borylation. The Suzuki
coupling of boronate 5v with several aryl bromides, catalyzed
by Pd(PtBu3)2 gave diarylmethanes 6d-f in good yield.
Comparison of Catalysts for the Benzylic Borylation of
Methylarenes Containing Hindered Aryl C-H Bonds. Be-
cause para-substitued toluenes do not contain any unhindered
aryl C-H bonds, we compared the selectivity obtained for the
borylation of these substrates under the conditions developed
in the current work to that obtained for aryl C-H borylation
under the conditions originally published by Ishiyama,
Miyaura, and Hartwig.32 We conducted the borylation of p-
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Page 6 of 12
Scheme 2. Functionalization of Benzylic Boronate Esters
(~80%). Triethylsilane was formed as a byproduct during this
reaction (see Figure S7).
1
2
3
4
5
6
7
8
n-BuLi 3 eq, MeONH2 3 eq,
then Boc2O 3 eq
Bpin
NHBoc
Complex 8 is kinetically competent to be an intermediate in
the benzylic borylation of methylarenes. The reaction of 2
with Et3SiBpin catalyzed by the silyl hydride chloride complex
3 at 80 °C occurred with a short induction period (~30 min).
However, the reaction of 2 catalyzed by diboryl silyl complex
8 occurred without an induction period (see Figure S8). This
lack of an induction period for the reaction catalyzed by 8 is
consistent with it being a reaction intermediate. The reaction
catalyzed by either complex formed benzylic boronate 2a in
61% yield with 11:1 Bn:Ar selectivity, as determined by gas
chromatography.
THF, -78 ºC to 65 ºC
6a, 49%
H2O2, NaOH
THF, H2O
KOtBu 3 eq,
then I2
THF, -78 ºC
ArBr 1.5 eq
OH
Pd(PtBu3)2 5 mol%
Cs2CO3 3 eq
Dioxane, H2O, 100 ºC
6b, 99%
9
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
6c, 86%
6d, Ar = C6H4-4-CN; 62%
6e, Ar = 3-py; 49%
6f, Ar = C6H4-4-OMe; 80%
Mechanistic Studies and Investigation of the Origin of
Selectivity. Having shown that the borylation reaction can be
diverted from aryl C-H bonds to benzylic C-H bonds by
changing the borane reagent and phenanthroline ligand on
iridium, we sought to reveal the origin of this new site selec-
tivity. First, we sought to reveal the effect of the reagent on
this site selectivity by determining the structure of the active
catalyst when conducting reactions with Et3SiBpin in place of
B2pin2. Second, we sought to reveal the origin of the electronic
effect of the ligand on the site selectivity. As part of this study,
we measured the rates for aryl C-H borylation and benzylic C-
H borylation with B2pin2 or Et3SiBpin catalyzed by iridium
complexes bound by dtbpy or L6. With the structure of the
active catalyst and detailed kinetic data as a foundation, we
computed the structure of the transition states for the steps that
cleave the C-H bond, form the B-C bond, and isomerize in-
termediates along the reaction coordinate.
N(2)
N(1)
Ir
B(2)
B(1)
Si
Figure 4. Structure of complex 8 determined by single-crystal X-
ray diffraction. Hydrogen atoms omitted for clarity. Selected bond
lengths (Å): Ir-N1 = 2.182(5), Ir-N2 = 2.195(5), Ir-B1 = 2.044(7),
Ir-B2 = 2.050(7), Ir-Si = 2.353(2). Selected bond angles (deg):
N1-Ir-Si = 93.2(1), N2-Ir-Si = 95.0(1), B1-Ir-Si = 86.3(2), B2-Ir-
Si =87.9(2).
Scheme 3. Order in Reagents for the Benzylic Borylation
of Methylarenes
F3C
CF3
F3C
CF3
Et3SiBpin 7.5 equiv
with or without 5 equiv
of COE
SiEt3
Et3SiBpin 0.30-0.60 M
Complex 8 0.0030-0.0090 M
N
N
N
N
H
Bpin
Bpin
Me
Ir
Ir
(3)
Cl
Bpin
THF, 80 ºC
45 min
3
SiEt3
6:1 MeCy:THF
8
80 ºC
5a
0.30-0.90 M
40% isolated
CF3
yield
F3C
CF3
F3C
Rate of Reaction: 1st order in [toluene], 1st order in [8], and 0th order
in [Et3SiBpin].
i. Isolation of the Resting State. The reaction of silyl catalyst
precursor 3 with 7.5 equivalents of Et3SiBpin in the presence
or absence of 5 equivalents of cis-cyclooctene (COE) led to
the isolation of iridium diborylmonosilyl complex 8 ligated by
L6 (Eq. 3). NMR spectral data indicated that this complex
lacked a bound alkene.36 Single crystals of complex 8 were
obtained, and the structure was determined by X-ray diffrac-
tion (Figure 4). Indeed, complex 8 adopts a slightly distorted
square-based pyramidal geometry in which the sum of the
angles in the square plane equals 360°, but the apical silyl
ligand is tilted slightly toward the boryl ligands (Si-Ir-B angles
= 86.3° and 87.9°). The Ir-B distances (2.044 and 2.050 Å) in
8 are similar to the Ir-B distances (2.027, 2.055, and 2.057 Å)
in the previously reported COE-bound dtbpy-complex contain-
ing three boryl ligands, rather than two boryl ligands and one
silyl ligand.
ii. Determination of the Rate Law. To determine the order of
the reaction in the different reagents, we measured the initial
rates of reactions of toluene with Et3SiBpin catalyzed by com-
plex 8 with varying concentrations of the three components.
The concentrations for this kinetic study are shown in Scheme
3 (also see Table S2 for a table of reaction conditions and ini-
tial rates). The rates of the reactions were determined to be
first order in toluene, zeroth order in Et3SiBpin, and first order
in complex 8. These orders are analogous to those for the
borylation of arenes with B2pin2 catalyzed by
(dtbpy)Ir(COE)(Bpin)3.37
iii. Reactivity of the Catalyst Resting State. Stoichiometric
reactions of complex 8 with methylarenes were conducted to
assess further the role of this complex in the catalytic system.
The reaction of fluorinated methylarene 10 with complex 8
(Figure 5a) forms a 1:1.4 ratio of benzylboronate to aryl-
boronate esters, as determined by 19F NMR spectroscopy (see
Figure S10 for the reaction profile). The yield of this stoichi-
ometric reaction was over 100% based on iridium, suggesting
that the Ir-byproducts of the reaction of 8 with 10 also react
with 10 to form boronate ester products. However, the catalyt-
ic reaction of 10 with Et3SiBpin catalyzed by complex 8 (Fig-
Complex 8 is the resting state of the iridium catalyst during
the benzylic borylation of methylarenes. Monitoring the
1
borylation reaction by H NMR spectroscopy during the reac-
tion of 4-chlorotoluene with Et3SiBpin catalyzed by complex 3
in methylcyclohexane-d14 (see SI, pp. S36-38) showed that
complex 8 was the major species ligated by L6 in solution
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Journal of the American Chemical Society
ure 5b) forms a 3:1 ratio of benzylboronate to arylboronate
complex 8 formed a 1.6 ± 0.3:1 ratio of benzylic boronate
esters, as determined by 19F NMR spectroscopy. This observa-
tion implies that complex 8 is not a true intermediate or it re-
acts in the absence of added silylborane by a pathway that is
distinct from the one by which it reacts in the presence of si-
lylborane.
products 5x and 15, respectively as determined by 19F NMR
spectroscopy after 15 minutes (<30% conversion of 8). The
analogous reaction of 13 and 14 with 10 equiv of Et3SiBpin
catalyzed by 8 gave a similar ratio of 5x to 15 (1.9 ± 0.3:1).
1
2
3
4
5
6
7
8
The same experiment conducted with the two methylarenes
14 and 16 gave a ratio of benzylic boronate products of 4.4 ±
0.6:1 (15:17) for the stoichiometric reaction and 4.2 ± 0.2:1
(15:17) for the catalytic reaction. The similar ratios for these
two competition experiments suggest that the active species
for benzylic borylation in the stoichiometric reaction is the
same as the active species for benzylic borylation in the cata-
lytic reaction.
F3C
CF3
F
F
Me
Br
Bpin
F
Me
+
Br
Br
N
N
Bpin
Bpin
Ir
a)
9
10
10 equiv
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SiEt3
11, 47%
Bpin
THF, 55 °C
8
12, 79%
F3C
CF3
Br
F
F
Thus, we favor the intermediacy of 8 in the borylation of
benzylic C-H bonds, rather than the conversion of 8 to a spe-
cies on a distinct catalytic cycle, for several reasons. First, the
selectivities are the same for the stoichiometric and catalytic
reaction of this complex with different benzylic C-H bonds.
Second, complex 8 is the only phenanthroline-bound species
F
Et3SiBpin
8 2 mol %
Me
Br
Br
Me
b)
Bpin
THF, 55 °C
11, 55%
Bpin
10
1.5 equiv
12, 18%
1
Figure 5. a) Reaction of complex 8 with 10. b) Reaction of 10
with Et3SiBpin catalyzed by complex 8. Yields determined by 19F
NMR spectroscopy.
observed by H NMR spectroscopy, and it reacts with rates
that are similar to those of the catalytic process. If a small
amount of complex generated from 8 were the true catalyst,
then the catalytic reaction must be significantly faster than the
stoichiometric reaction to account for the higher Bn:Ar selec-
tivity observed during the catalytic reaction than during the
stoichiometric reaction. Third, our data show that the rate of
aryl borylation differs in the catalytic and stoichiometric reac-
tion, not the rate of benzylic borylation. The catalytic boryla-
tion of arenes is slower than the stoichiometric borylation of
arenes because the silylborane inhibits the aryl C-H borylation
reaction.
To reveal the origin of the difference in selectivity between
the stoichiometric reaction of complex 8 with arene 10 and the
catalytic reaction, we determined the rate law for formation of
aryl and benzyl boronates from the reaction of 8 with 10. The
rate of borylation of aryl and benzyl C-H bonds are both first
order in arene 10 and first order in iridium complex 8. Howev-
er, the rate of benzylic C-H borylation is independent of the
concentration of Et3SiBpin, while the aryl C-H borylation is
approximately inverse-first order in the concentration of
Et3SiBpin at low ratios of Et3SiBpin to Ir (Figure 6). At high
ratios of Et3SiBpin:Ir, the arene borylation was zero order in
Et3SiBpin. Thus, the effect of the concentration of Et3SiBpin
on the selectivity of the reaction of 8 with 10 results from the
suppression of the rate of arene borylation by the Et3SiBpin
that is present in the catalytic reaction. These data are con-
sistent with the intermediacy of 8 and a change in the selec-
tivity of the reaction of 8 in the presence and absence of
Et3SiBpin.
Scheme 4. Competition Experiments for the Borylation of
Fluorinated Methylarenes with Complex 8 and with
Et3SiBpin Catalyzed by 8a
Me
Bpin
F
F
F
Br Bpin
13
10 equiv
Me
F
+
complex 8
1 equv
Br
Br
F
15
Br
THF, 55 ºC
15 min
Me
Me
6.00E-06!
5.00E-06!
5x
without Et3SiBpin 1.6 ± 0.3 : 1
with 10 equv Et3SiBpin 1.9 ± 0.3 : 1
14
10 equiv
F
4.00E-06!
Benzylic C-H
Borylation!
Br
3.00E-06!
2.00E-06!
Me
Me
Me
F
Bpin
Br Bpin
Aryl C-H Borylation!
14
10 equiv
Me
Me
complex 8
1 equiv
+
F
F
1.00E-06!
0.00E+00!
F
15
THF, 55 ºC
15 min
Me
17
0!
0.05!
0.1!
0.15!
[Et3SiBpin] (M)!
16
10 equiv
without Et3SiBpin 4.4 ± 0.6 : 1
with 10 equiv Et3SiBpin 4.2 ± 0.2 : 1
Figure 6. Dependence of the rate of aryl and benzylic C-H
borylation on the concentration of Et3SiBpin. Reactions conducted
with 8 (14 mM), 10 (72 mM), and Et3SiBpin (0-0.13 M) in THF.
Initial rates for the formation of 11 and 12 were determined by 19
aReactions were conducted on a 0.0043 mmol scale. Ratios of
products were determined by 19F NMR spectroscopy.
F
The origin of the difference in rate of arene borylation in the
presence and absence of added Et3SiBpin is unclear, but it may
be due to the presence of complexes in equilibrium with 8 that
can react with arenes to form aryl boronate esters. The for-
mation of these complexes may be suppressed in the presence
silylborane. Although we have been unable to identify such
NMR spectroscopy.
The intermediacy of 8 in the benzylic borylation is also
supported by experiments that compare the selectivity of the
stoichiometric and catalytic reaction for the borylation of dif-
ferent fluorinated methylarenes (Scheme 4). The reaction of
10 equivalents each of the two methylarenes 13 and 14 with
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Journal of the American Chemical Society
Page 8 of 12
species, one possibility is the formation of a trisboryl complex Thus, the rate of borylation of electron-deficient methylarenes
1
2
3
4
5
6
7
8
by disproportionation of the silyldiboryl complex 8 initiated
by reversible reductive elimination of Et3SiBpin or generation
of a highly reactive Ir(I) boryl species by the same reversible
reductive elimination of Et3SiBpin. This trisboryl complex
would then react rapidly with an aryl C-H bond.
is faster than the rate of borylation of electron-rich
methylarenes.
The analogous effect of the electronic properties of the
arene on the borylation of an aryl C-H bond with Et3SiBpin as
the reagent catalyzed by complex 8 was measured by conduct-
ing the borylation of 1,3-disubstituted arenes. The rho value
from these studies was 3.3, which is larger than the rho value
obtained from the benzylic borylation of methylarenes. This
result indicates that the rate of the borylation of aryl C-H
bonds is more sensitive to the electronic properties of the
arene undergoing functionalization than is the rate of boryla-
tion of benzylic C-H bonds. This result explains why the
Bn:Ar selectivity for the borylation of electron-poor
methylarenes is lower than that for the borylation of electron-
rich methyl arenes.
iv. Investigation of the Turnover-Limiting Step. If oxidative
addition of a C-H bond is the turnover-limiting step in the
iridium-catalyzed borylation of benzylic C-H bonds with
Et3SiBpin, one would expect to observe 1) a primary kinetic
isotope effect, 2) faster benzylic borylation of electron-
deficient methylarenes than of electron-rich methylarenes, and
3) faster rates for the benzylic borylation of methylarenes cata-
lyzed by electron-rich Ir complexes than by electron-poor Ir
complexes. Experimental and theoretical studies on the iridi-
um-catalyzed borylation of arenes with B2pin2 have shown
previously that oxidative addition of an aryl C-H bond is the
turnover-limiting step of that process.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The effect of the electron-density at iridium on the rate of
benzylic and aryl C-H borylation was revealed by conducting
the catalytic borylation of 1,3-di-tert-butylbenzene and me-
sitylene with B2pin2 or Et3SiBpin catalyzed by a series of iridi-
um complexes. We conducted these reactions with the four
iridium catalysts 8, 18-20, which are trisboryl complexes (18
and 20) and diborylmonosilyl complexes (8 and 19) bound by
L6 (8 and 18) and by dtbpy (19 and 20). Trisboryl complexes
have been shown previously to be intermediates in the boryla-
tion reactions conducted with B2pin2 as the boron-containing
reagent, and diborylmonosilyl complexes appear to be the
active catalysts during borylation reactions conducted with
Et3SiBpin as the boron-containing reagent.
The kinetic isotope effect for benzylic borylation was de-
termined by measuring the rate of the catalytic borylation of
toluene and toluene-d8 in separate vessels. In contrast to the
large primary isotope effect (5.0) for the iridium-catalyzed
borylation of benzene,36 the isotope effect from the independ-
ent reactions of toluene and toluene-d8 with Et3SiBpin cata-
lyzed by 8 was only 2.2. Although a KIE of 2.2 could imply
that C-H oxidative addition is the turnover-limiting step, this
value is lower than most kinetic isotope effects for reactions
occurring with rate-limiting C-H bond cleavage.
Et3SiBpin 1 equiv
Complex 8, 1 mol%
Rxn. A
Me
Table 2. Effect of Different Catalysts on the Rate Constant of
Bpin
Benzylic C-H Borylation and Aryl C-H Borylationa
6:1 Me-Cy:THF
80 ºC
R1
R1
R2
2 equiv
2 equiv
boron reagent 1 equiv
Ir cat.1 mol%
tBu
tBu
tBu
tBu
Rxn. B
R2
Et3SiBpin 1 equiv
Complex 8, 0.3-1 mol%
Aryl
R3
R3
Borylation
6:1 MeCy:THF
80 ºC
2 equiv
Bpin
6:1 Me-Cy:THF
80 ºC
Bpin
boron reagent 1 equiv
Ir cat.1 mol%
Me
Me
Me
Bpin
Benzylic
Borylation
6:1 MeCy:THF
80 ºC
Me
Me
2 equiv
ꢀꢁꢂꢁꢃꢄꢅ
R1= CF3
R2= R3= CF3
Aryl Borylation
Benzylic Borylation
ΔG‡Bn−ΔG‡
Ar
R2= Cl
R3= CF3
k
k
R1= Cl
(corrected for #
of C-H bonds)
Ir cat./reagent
krel
krel
(M-1s-1
)
(M-1s-1
)
R1= H
R1= iPr
8/Et3SiBpin 1.36(7) x 10-4
9.2(4) x 10-3 67
19/Et3SiBpin 2.85(4) x 10-4 2.1
1.25(5) x 10-1 919
1
6.3(2) x 10-3
2
-1.2 kcal/mol
+2.2 kcal/mol
-0.3 kcal/mol
+4.1 kcal/mol
R2= Cl
Rxn A: Benzylic
R3= OMe
C-H Borylation
18/B2pin2
3.4(3) x 10-3 1.1
3.8(1) x 10-3 1.2
ꢀꢁꢂꢁꢆꢄꢆ
Rxn B: Aryl C-H
Borylation
R2= R3= tBu
20/B2pin2
3.2(1) x 10-3
1
Figure 7. Hammett correlation for the benzylic C-H borylation of
para-substituted toluenes and the aryl C-H borylation of 1,3-
disubstituted arenes. Reactions conducted on a 0.125 mmol scale.
The formation of aryl and benzylic boronate esters was monitored
by gas chromatography.
Ligand
X
Ir cat.
Ir cat.
8
L6
SiEt3
Bpin
SiEt3
Bpin
Bpin
Bpin
18c
19d
20e
L6
(Ligand)
Ir
dtbpy
dtbpy
X
The effect of the electronic properties of the methylarenes
on the cleavage of the benzylic C-H bond was revealed by
aReactions were conducted on a 0.125 mmol scale. Formation of
aryl and benzylic boronate esters monitored by gas chromatog-
raphy. bReaction conducted with 2 mol% catalyst. cFormed in situ
from L6 and (η6-mes)Ir(Bpin)3.39 dFormed in situ from
conducting reactions of
a
series of para-substituted
methylarenes with Et3SiBpin catalyzed by complex 8. The
initial rates for the formation of the benzylic boronate esters
was correlated with Hammett substituent constants calculated
from the 19F NMR chemical shifts of substituted fluoroben-
zenes (Figure 7).38 The rho value from this correlation was 2.1.
e
(dtbpy)IrCl(SiEt3)H and Et3SiBpin. Formed in situ from dtbpy
and (η6-mes)Ir(Bpin)3.
8
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The second-order rate constants for the aryl C-H borylation
ln kobs for the borylation of aryl C-H bonds decreases with
increasing νCO, while ln kobs for benzylic borylation changes
little with increasing νCO. The difference in these trends ex-
plains why the ratio of benzylic borylation to aryl borylation
for reactions catalyzed by complex 8 is larger than the corre-
sponding ratio for reactions catalyzed by the more electron-
rich iridium catalysts. The catalyst containing a less electron-
rich metal center undergoes borylation of the aryl C-H bond
more slowly than that containing the more electron-rich metal
center, but the rate of the borylation of benzylic C-H bonds is
not sensitive to the degree of electron density at the metal cen-
ter. The origin of this difference in electronic effects was re-
vealed by DFT calculations.
1
2
3
4
5
6
7
8
of 1,3-di-tert-butylbenzene and for the benzylic C-H boryla-
tion of mesitylene were obtained by the method of initial rates,
and the values are given in Table 2. These data show that the
rate constants for benzylic borylation vary little with the
change in boron source and the electronic properties of the
iridium catalyst. In contrast, the rate constants for aryl C-H
borylation span nearly three orders of magnitude.
From the rate constants for reactions conducted with each
combination of catalyst and reagent, we calculated the differ-
ence in overall barrier for the borylation of a single benzylic
C-H bond of mesitylene and the barrier for the borylation of a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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31
32
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60
single aryl C-H bond of 1,3-di-tert-butylbenzene (ΔG‡
-
Bn
ΔG‡Ar). For reactions in which the active catalyst is expected
to be an Ir-diboryl monosilyl complex (reagent = Et3SiBpin,
catalyst = 8 or 19) the borylation of a benzylic C-H bond was
preferred over the borylation of an aryl C-H bond. The reac-
tions catalyzed by 8 occurred with the largest preference
(ΔG‡Bn-ΔG‡Ar = -1.2 kcal/mol) for reaction at the benzylic C-H
bonds over the aryl C-H bonds. However, for reactions in
which the active catalyst is expected to be a trisboryl complex
(reagent = B2pin2, catalyst = 18 or 20) the borylation of an aryl
C-H bond of 1,3-di-tert-butylbenzene is strongly favored over
v. Investigation of the Turnover-Limiting Step by DFT. Alt-
hough the KIE and the rho value for benzylic borylation are
consistent with turnover-limiting C-H oxidative addition, the
lack of an influence of the electron-density at Ir on the rate of
benzylic borylation argues against turnover-limiting oxidative
addition of a C-H bond. Recently, Himo et al conducted a
computational study on the mechanism of the borylation of the
C-H bonds in chlorosilanes, and they determined that an isom-
erization process occurs prior to reductive elimination to form
the C-B bond. This isomerization process yields an intermedi-
ate that is computed to undergo reductive elimination with a
barrier that is lower than that for reductive elimination without
isomerization.40 This isomerization was computed with the
B3LYP-D3 functional to be the turnover-limiting step, but
oxidative addition of the C-H bond was computed with the
M06 functional to be turnover limiting.
the borylation of a benzylic C-H bond of mesitylene (ΔG‡
ΔG‡Ar = +2.2-4.1 kcal/mol).
-
Bn
Table 3. C-O Stretching Frequencies of Carbonyl-Bound
Ir-Trisboryl and Ir-Diborylmonosilyl Complexesa
υCO (cm-1
1985
)
Ligand
X
Ir-CO
21
Ir-CO
(Ligand)
L6
SiEt3
Bpin
SiEt3
Bpin
CO
Bpin
Bpin
22
L6
1977
We calculated possible reaction pathways for the borylation
of a benzylic C-H bond of toluene with complex 8. The struc-
tures of intermediates and transition states were optimized
using the B3LYP functional with Grimes’ dispersion correc-
tion (B3LYP-D3) with the lanl2dz basis set for Ir and the 6-
31G(d,p) basis set for all other atoms. Single-point energy
calculations with a solvent correction (cyclohexane, IEFPCM)
were conducted with the M06 functional with the lanl2tz basis
set for Ir and the 6-31++G** basis set for all other atoms.41
Ir
23
dtbpy
dtbpy
1981
X
24
1972
aMeasured by solution (THF) IR spectroscopy.
To assess the relative electron-density at iridium in com-
plexes 8 and 18-20, we synthesized the CO adducts 21-24
(Table 3) and measured their νCO values (in THF). These val-
ues indicate: 1) complex 8 is the least electron-rich of the four
complexes; 2) dtbpy is more electron donating than L6; 3) the
Bpin ligand is more donating than the SiEt3 ligand; and 4) the
difference between a silyl ligand and boryl ligand on the metal
affected the electron density more than the difference between
the dative ligands.
N
= L6
N
Ir
‡
N
N
Bpin
Bpin
Ph
N
Ph
N
Bpin
Bpin
Ir
H
H
Ir
SiEt3
N
Bpin
SiEt3
N
+ PhCH3
Bpin
SiEt3
I
0.0
II
17.3
TS-I
24.1
‡
Ph
N
PhCH2Bpin
+
Bpin
N
N
N
Bpin
H
H
Bpin
Path A
Ir
Ir
Ir
OR
Bpin
H
N
N
SiEt3
SiEt3
Et3Si
Ir cat. = 20
Ir-CO = 24
Ir cat. = 18
Ir-CO = 22
IV
4.5
TSa-II
II
28.0
Ir cat. = 19
Ir-CO = 23
Ir cat. = 8
Ir-CO = 21
‡
‡
Ph
N
Ph
N
Ph
N
Bpin
H
Bpin
H
Bpin
H
Figure 8. Dependence of the ln kobs for benzylic and aryl C-H
borylation on the electronic properties of the catalyst. Rate con-
stant (kobs) determined for the benzylic C-H borylation of mesity-
lene and the aryl C-H borylation of 1,3-di-tert-butylbenzene cata-
lyzed by complexes 8, 18-20. C-O stretching frequency deter-
mined for complexes 21-24.
Ir
Ir
Ir
Path B
N
N
N
Bpin
Bpin
SiEt3
Bpin
SiEt3
SiEt3
TSb-II
24.9
III
11.3
TSb-III
15.6
Figure 9. Computed pathways for the benzylic borylation of tolu-
ene with complex 8. Structures optimized at B3LYP-D3 level
with lanl2dz (Ir) and 6-31G(d,p) basis sets. Single-point energy
calculations conducted at M06 level with lanl2tz (Ir) and 6-
A plot of the ln kobs for the reactions catalyzed by the corre-
sponding complexes 8 and 18-20 versus the νCO values for
complexes 21-24 is shown in Figure 8. This graph shows that
9
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Page 10 of 12
N
31++G** basis sets and a solvent correction (cyclohexane,
IEFPCM). Values given for Gibbs free energy (kcal/mol)..
= L6
Ar-CH3
1
2
3
4
5
6
7
8
N
N
Bpin
Bpin
Ir
We considered two pathways (Figure 9) that begin with di-
boryl silyl complex I and proceed through the transition state
for oxidative addition of a benzylic C-H bond TS-I to form the
seven-coordinate intermediate II containing a partial B-H
bond. In one pathway (Path A) intermediate II reacts through
the transition state TSa-II for reductive elimination to form
the B-C bond in benzyl boronate ester and iridium product IV.
In a second pathway (Path B) intermediate II undergoes isom-
erization through transition state TSb-II in which the hydride
is exchanged between the boryl ligands, forming intermediate
III. Intermediate III then undergoes reductive elimination to
form the boronate ester and product IV through transition state
TSb-III.
N
Et3SiBpin
SiEt3
8
Ar
N
Et3SiH
N
Ir
N
H
Bpin
Bpin
Ir
H
N
Bpin
SiEt3
SiEt3
Ar
N
Bpin
H
9
Ir
Turnover-Limiting
Step
Ar
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bpin
SiEt3
Bpin
CONCLUSION
We have shown that the selective borylation of the benzylic
C-H bonds of methylarenes can be achieved with Et3SiBpin as
reagent and an iridium catalyst containing a more weakly do-
nating dative ligand than the commonly used di-tert-
butylbipyridine. Unlike previously reported methods for the
borylation of benzylic C-H bonds, our method occurs with
good functional group tolerance and occurs without the need
for a directing group or solvent quantities of the methylarene.
The benzylic boronate esters formed during this reaction un-
dergo a series of transformations to form diverse products.
Our calculations predict that Path B is favored over Path A
by 3.1 kcal/mol. In Path B, the transition state for isomeriza-
tion through TSb-II prior to reductive elimination (TSb-III) is
computed to lie at a slightly higher energy than that for the C-
H bond cleavage. In contrast to Himo’s calculations, our cal-
culations find that the isomerization step is higher in energy
than C-H activation when either the M06 or the B3LYP-D3
functionals are used (see SI, pg. S56 for B3LYP-D3 energies).
To probe these relative energies, we compared our experi-
mental KIE to the theoretical KIE calculated for Path A and
Path B (see SI, pp. S57-60). The theoretical kinetic isotope
effects for Path A and Path B were calculated to be 1.5 and
1.8, respectively. Although the difference is small, the isotope
effect calculated for Path B is closer to the experimental value
of 2.2.
The key to the development of this reaction was the discov-
ery of an iridium diborylmonosilyl complex that is more elec-
tron-deficient than the previously reported iridium trisboryl
complex for C-H borylation. This reduced electron density at
the metal center significantly reduced the rate of aryl C-H
borylation while not significantly affecting the rate of benzylic
C-H borylation. This difference in effect of electronic proper-
ties on the rate of borylation appears to result from a differ-
ence between the turnover-limiting step for aryl C-H boryla-
tion and benzylic C-H borylation.
The relative energies of these transition states suggest that
the isomerization could be the rate-limiting step of the ben-
zylic borylation. Consistent with this hypothesis, the benzylic
borylation is relatively insensitive to changes in electron-
density at iridium. This electronic effect is consistent with a
rate-limiting, redox-neutral isomerization, rather than an oxi-
dative addition of a C-H bond. In contrast, the sensitivity of
the aryl C-H borylation to electron-density at iridium is con-
sistent with turnover-liming oxidative addition of the C-H
bond. In other words, the effect of the electron-density of the
Ir catalyst on the selectivity of the reaction is consistent with a
difference in the turnover-limiting step of the borylation of
aryl C-H bonds and the borylation of benzylic C-H bonds.
The ancillary dative ligand and one of the X-type ligands in
the iridium diborylmonosilyl catalyst 8 of the current work are
different from those of the iridium trisboryl IMH catalyst 20.
Instead of the strongly electron-donating dtbpy as the ancillary
ligand in 20, a less electron-donating L6 is the ancillary ligand
in catalyst 8, and instead of three boryl groups in 20, one less
electron-donating triethylsilyl ligand and two boryl ligands are
present in catalyst 8. Both of these differences in the ligands
cause the electron density at iridium in complex 8 to be less
than that in the IMH catalyst 20. This difference in electron
density gives rise to the ca. 5 kcal/mol difference in the value
of ΔΔG‡ for the borylation of the two types of C-H bonds cata-
lyzed by 8 and by 20.
Our study, as well several recent reports,42-45 demonstrates a
direction for the design of new iridium catalysts for the boryla-
tion of C-H bonds. In the IMH catalyst, boryl ligands are both
reactive and ancillary ligands. In the system we report here,
one of the ancillary boryl ligands is replaced by a silyl ligand,
thereby changing the electronic properties of the metal center
for cleavage of the C-H bond. This property leads to novel
selectivity for C-H borylation, and we are currently investigat-
ing the effect of altering the electronic and steric properties of
the ancillary silyl ligand on the selectivity for various classes
of C-H bond functionalization reactions.
Based upon our experimental and computational data we
propose that the benzylic borylation of methylarenes catalyzed
by complex 8 occurs via the mechanism detailed in Scheme 5.
From the resting state 8, reversible oxidative addition of a
benzylic C-H bond of the methylarene occurs, followed by an
irreversible isomerization. Reductive elimination then forms
the benzylic boronate ester, and the catalyst is regenerated by
reaction with Et3SiBpin to form the Et3SiH byproduct.
Scheme 5. Proposed Mechanism for the Benzylic C-H
Borylation of Methylarenes with Et3SiBpin Catalyzed by
Complex 8
ASSOCIATED CONTENT
Supporting Information.
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Journal of the American Chemical Society
(29) Ohmura, T.; Torigoe, T.; Suginome, M. Chem. Comm. 2014, 50,
6333.
(30) Ohmura, T.; Torigoe, T.; Suginome, M. J. Am. Chem. Soc. 2012,
Experimental procedures and spectra for all new compounds,
1
2
3
4
5
6
7
8
cartesian coordinates and energies of calculated ground states and
transition states, crystallographic information, and CIF files. This
material is available free of charge via the internet at
http://pubs.acs.org.
134, 17416.
(31) Moore, D. S.; Robinson, S. D. Chem. Soc. Rev. 1983, 12, 415.
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AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
(34) Hong, K.; Liu, X.; Morken, J. P. J. Am. Chem. Soc. 2014, 136,
10581.
(35) Pidathala, C.; Amewu, R.; Pacorel, B.; Nixon, G. L.; Gibbons, P.;
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Srivastava, A.; Shone, A. E.; Charoensutthivarakul, S.; Taylor, L.; Berger,
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(37) The rate of C-H borylation of arenes with B2pin2 catalyzed by
(dtbpy)Ir(COE)(Bpin)3 is half order in catalyst in the absence of added
COE and first order in catalyst in the presence of added COE.
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1735.
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Soc. 2014, 136, 4575.
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Soc. 2014, 136, 14345.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the NSF (CHE-01213409 to JFH and CHE-0840505 to
the Molecular Graphics and Computation Facility at UC Berke-
ley) for support of this work, and Dr. A. DiPasquale for X-ray
crystallography. We thank Johnson Matthey for a gracious dona-
tion of [Ir(COD)OMe]2.
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2
3
For Table of Contents Only
4
5
6
7
8
9
O
F3C
CF3
B
SiEt3
O
O
O
1.0 equiv
Ir cat. 1-2 mol%
B
N
N
Me
X2
X1
Ir
R
R
MeCy
100 ºC
SiEt3
1.5 equiv
35-87%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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32
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34
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36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
27 examples
1.7-99:1 selectivity
CF3
F3C
Ir precat: X1 = H, X2 = Cl
Active cat: X1 = X2 = Bpin
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